Understanding how the normal brain develops and what goes wrong in disease is fundamental for designing better ways to prevent congenital diseases, and to treat degenerative disorders marked by neuronal loss. Of particular relevance to this application, there is a growing recognition that heterotrimeric G proteins are critical for formation and maintenance of the brain. They produce bifurcating signals in the form of a GTP- subunit and a dimer that regulate phospholipases, adenylyl cyclases, and ion channels to produce the second messengers responsible for modulating many neuronal processes. The current challenge is to relate the individual G-protein subtypes to their regulation of particular processes. Both expression and functional evidence suggest the Gng5 gene encoding the G-protein gamma5 subunit plays a critical role in modulating proliferation, migration, or differentiation. Gng5 is preferentially expressed in neural progenitor cells. Moreover, we have shown that global deletion of Gng5 causes microcephaly. However, the information that can be obtained from studying the global knockout mice has been limited by their early embryonic lethality resulting from a cardiac defect. Consistent with the stated purpose of the R03 mechanism, this application proposes to develop a conditional knockout mouse model in which Gng5 is specifically deleted in neural progenitor cells. This will be accomplished by crossing mice carrying two floxed Gng5 alleles with transgenic mice expressing Cre-recombinase under control of the nestin promoter. Subsequently, histological analyses of conditional knockout brains will be performed to identify how loss of the G-protein ?5 subunit affects cortical size and organization, while molecular strategies will be used to elucidate any underlying defects in proliferation, migration, or differentiation of neural progenitor cells. Revealing the signaling pathways requiring the G-protein ?5 subunit that is responsible for neural progenitor cell expansion, migration, or differentiation may provide a molecular basis for the future development of effective strategies to prevent congenital disorders and treat neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: To improve the health of the American people, the goal of both NINDS and NICHD are to gain a better understanding of how the normal brain develops, and to translate these discoveries into better strategies to prevent congenital disorders, and to more effectively treat neurodegenerative disorders. This R03 application addresses both goals by providing a novel mouse model for studying how heterotrimeric G proteins are involved in formation and maintenance of brain. This resource will have inherent value to both the neuroscience and development communities.